Novel 17-ketals of 1-substituted-4-alkylated estra-1, 3, 5(10)-trienes



United States Patent 3,138,537 NOVEL 17-KETALS 0F I-SUBSTITUTED-l-ALKYL- A'IEl) ESTRA-1,3,5(10)-TRIENES Leland L. Smith, Malvern, Pa.,assignor to American Home Products Corporation, New York, N.Y., acorporation of Delaware No Drawing. Filed Aug. 24, 1962, Ser. No.219,129

11 Claims. (Cl. 260-2395) This invention relates in general to a novelseries of 17-ketals of 1,4-substituted estra-1,3,5(l0)-triene, methodsof preparing the same, intermediates and pharmaceutical compositionscontaining these novel compounds.

The compounds of the invention may be more particularly described byreference to the general formula:

wherein R represents a substituent selected from the group consisting ofhydrogen, lower alkyl, lower alkenyl, lower cycloalkyl, lower aralkyl,and acyl; R represents lower alkyl; and W represents a member selectedfrom the group consisting of alkylenedioxymethylene,alkylenethioxymethylene and alkylenedithiomethylene.

In the above definition the term lower alkyl as employed herein refersto those alkyl groups having from about 1 to 20 carbon atoms, and moreparticularly to those having less than about 10 carbon atoms. The alkylgroup may be normal or branched in structure although the normal chainis generally preferred. Some examples of these alkyl groups would bemethyl, ethyl, propyl, butyl, isopropyl, isobutyl, pentyl, octyl,dodecyl and cetyl to name a few of such substituents. The term lowercycloalkyl refers to that substituent wherein the carbon atoms arejoined in a carbocyclic ring which is generally a 5 or 6 membered ringbut which may contain a smaller or larger number of carbon atoms subjectto the practical limits of stability of such structures. Cyclohexanewould be an example of a preferred member of this class of substituents.The term lower aralkyl refers in general to an alkyl group of from about1 to 20 carbon atoms substituted by an aromatic ring structure. Aninstance of this type of substituent would be benzyl, phenylethyl,phenylisopropyl, and the like. By the term lower alkenyl as it isemployed herein, it is intended to refer to those unsaturatedhydrocarbon radicals containing at least one double bond in the chainsuch as allyl, vinyl, and the like. In the present usage this termembraces all such radicals having less than about 20 carbon atoms andpreferably less than about carbon atoms.

An essential portion of our novel structure is the substitutionindicated by W in the l7-position of the steroid molecule. It isintended by the definition of alkylenedioxymethylene as employed todefine W that it embrace such ketals containing up to about 10 carbonatoms but preferably not more than about 4 carbon atoms. By the termalkylenethioxymethylene it is intended to include those ketals where oneoxygen atom of the structure has been replaced by a sulfur atom. In acorresponding manner the term alkylenedithiomethylene as it is employedherein refers to those ketals wherein both oxygen atoms have beenreplaced by a sulfur atom.

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The novel compounds of the invention may be prepared by means of thefollowing general method:

CH3 CH3 The known starting material 1-hydroxy-4-methylestra- 1,3,5(l0)-trien-17-one (I) may be ketalized with a suitable ketalizing agentsuch as ethylene glycol (or other alkylene glycol, as 1,3-propanediol,etc.) in a solvent such as benzene with a condensing agent such asp-toluenesulfonic acid at temperatures up to the reflux temperature ofthe solvent employed for from about 2 to 24 hours duration in such amanner as to produce the 17-ethylene ketal (II), which in turn may serveto lead to the l-ethers, represented in the above diagram as thel-methyl ether (III), by etherification such as by the action ofdimethyl sulfate and alkali on the l-phenol (II). Other l-alkyl etherscan be prepared by use of other alkylating agents as described in theexamples herein appended. As an alternative procedure to esterify, thel-phenol (II) may be acylated with a suitable acylating agent, such asacetic anhydride in pyridine, to form the l-acetoxy ketal (IV). Otheracylating agents such as propionic anhydride, benzoyl chloride, etc. inpyridine may be used to afford the respective l-esters.

In the preparation of the 17-ketals of this invention as illustratedabove only one of a plurality of possible methods of ketalization hasbeen disclosed. It should be I understood that within the generalframework of the invention other alternative means of ketal formationmay be employed if desired. For instance the process of 17- ketalizationto form these novel compounds may be carried out by an exchange reactionwhich is known as exchange ketalization. In this method the 17-ketone tobe ketalized is contacted with the ketal of another carbonyl compoundsuch as the ethylene ketal of acetone, methylethylketone, mesityl oxideor the like in the presence of an acidic catalyst to effect a transferof the ketal function from the latter compound to the former one. Thisreaction may be conducted either in the presence or absence of heatingas specific conditions dictate. In any event one is thus able to obtainthe l7-ketals of the invention.

It should further be noted that the present invention also comprehendsthe preparation of so-called .open

chain l7-ketals wherein the carbon atoms attached to the oxygen orsulfur atoms are not in fact joined together. However the preparation ofcompounds such as these will become clear to those skilled in the artafter consideration of the foregoing disclosure.

The compounds of the invention are useful in the field 1 3 ofexperimental pharmacology as well as being valuable intermediates forfurther steroid synthesis in preparing new steroidal compounds. Inaddition, many of the compounds of the invention have been found todemonstrate high antilipemic properties coupled with low feminizingaction. Also, besides having capacity to regulate blood lipids, thecompounds are useful for their general hormonal effect, particularly inthe female. Therefore many of the compounds would be expected to exhibitutility in those areas where estrogens are employed, such as femalehypogonadism, amenorrhea, dysmenorrhea metrorrhagia, ovulation block andcontraception, pregnancy maintenance, arteriosclerosis, osteoporosis,menopausal symptoms, infertility, regulation of Water balance,functional uterine bleeding, and the like.

The novel compounds of the invention when contemplated for use inpharmaceutical products, may be admixed and administered in combinationif desired with a. large number of compatible diluents, carriers and thelike to form a pharmaceutical composition. Such Wellknown liquidcarriers as mineral or vegetable oil or a lower aliphatic alcohol may beused Where injectables are to be prepared. Glycerine or the like may beused Where the compound is to be administered as a syrup. Solidexcipients, binders, extenders or carriers such ascarboxymethylcellulose, starches, sugars and the like may be added wheretablets or powders are to be employed as a means of administration. Thedosage of the compounds will vary with the severity of the ailment andin general can vary from about 0.5 to 100 mg./kilo of body Weight perday depending upon the many factors of the case involved.

While the foregoing flow diagrams generally illustrate a means ofobtaining the various compounds of the invention, there is no doubt thatothers will be brought to mind. It is applicants intention to claim allof these structures. The following examples serve only to illustrate themethod of preparing some specific compounds of this series. It is to beunderstood that for a proper legal definition of the invention,attention must be directed only to the several appended claims.

EXAMPLE 1 17,1 7-Ethylelzedi0xy-4-Methylestra-1,3,5(10) T rien-I -OlReflux a. mixture of 485 mg. ofl-hydroxy-4-methytestra-1,3,5(10)-trien-17-one, 85 mg. ofp-toluenesulfonic acid, 50 ml. of benzene, and 5 ml. of ethylene glycolwith removal of water via a Dean-Stark apparatus for 20 hours. Wash thecooled mixture with saturated potassium bicarbonate solution, Withwater, and finally dry over anhydrous magnesium sulfate. The evaporatedbenzene solution will yield 550 mg. of solids, M.P. 234-235 lacking inabsorption near 5.85 4. Recrystallization of the solids from ethylacetate Will give the pure product, M.P. 240-2405; [l1] +138; x 222 mu.(6 7,700, shoulder), 282-288 mu (6 2,300);

3.00 3.45 6.30 1, 6.74 6.877., etc.

Analysis.Calcd. for C H O C, 76.79; H, 8.59. Found: C, 76.82; H, 8.52.

Thin-layer chromatography using silica gel chromatoplates developed withhexane-ethyl acetate (4:1) and (1:1) will show a single spot at R 0.17and 0.74 respectively, positive (bluish-violet) to phosphomolybdic acid1-hydr0xy-4-methylestra-l,3,5 -trien-l7-one has R 0.12 and 0.72respectively.

EXAMPLE 2 1 7,17-Ethylenedi0xy-1-Meth0xy-4-Met/1ylestra- 1,3,5(10)-Triene Treat a solution of 500 mg. of 17,17-ethylenedioxy-4-methylestra-1,3,5(10)-trien-1-ol in 75 ml. of boiling methanol with 175ml. of 10% aqueous sodium hydroxide solution dropwise. Then add 25 ml.of dimethyl sulfate dropwise over a 20-minute period. Add a second 175ml. portion of sodium hydroxide solution and a second 25 ml. portion ofdimethyl sulfate, keeping the solution at boiling point during theseveral additions. Cool the mixture, and dilute with 200 ml. of water.Filter the precipitated product and dry in air.

EXAMPLE 3 LLtlzoxy-J 7,1 7 -Eetl1yIenedz'oxy-4-M ethyleslra-1,3,5(10)-Triene Treat a solution of 500 mg. of 17,l7-ethylenedioxy-4methylestra-1,3,5(10)-trien-1-o1 in 25 m]. of absolute ethanol with 5ml. of ethyl bromide and 300 mg. of sodium hydroxide. Reflux the mixturefor 15 hours, then evaporate the solvent under vacuum. Dissolve theresidue in carbon tetrachloride and wash the solution with 5% sodiumhydroxide solution, then with water. The carbon tetrachloride is thenremoved under vacuum, and the solid residue is crystallized fromacetone.

EXAMPLE 4 -Cycl0pent -'l0xy"17, l 7-Ethy1enedioxy-4-Met/1ylestra- 1,3,5(10)-Trims EXAMPLE 5 1-Allyl0xy-1 7,] 7-Ezhylenedi0xy-4-Methyleslra-],3,5,(10)-Triene Treat 500 mg. of 17,17-ethylenedioxy-4-methylestra-1,3,5(10)-trien-1-ol with 15 ml. of ethanol, 5 ml. of allyl bromide andmg. of sodium hydroxide. Refiux the mixture for 18 hours, after whichtime remove the organic solvents under vacuum. Dissolve the solidresidue in carbon tetrachloride, and wash the carbon tetrachloridesolution with 5% sodium hydroxide solution and then with water. Thecarbon tetrachloride may then be removed under vacuum and the solidproduct dissolved in methanol. Concentrate the methanol solution untilcrystallization begins, then refrigerate to complete the precipitationof product. The crystalline product is then recovered by filtration.

EXAMPLE 6 1 -Benzyl0xy-1 7,1 7-Ethylenedl'0xy-4-Methy1eslra-1,3,5(10)-Triene Reflux a mixture of 500 mg. of 17,17-ethylenedioxy-4-methylestra-1,3,5(10)-trien-1-ol, 25 ml. of ethanol, 5 ml. of benzylbromide, and 200 mg. of sodium hydroxide for 15 hours. Remove thesolvents under vacuum and take up the solid residue in carbontetrachloride. Wash the carbon tetrachloride solution with 5% sodiumhydroxide solution and then with Water. Dry the carbon tetrachloridesolution over anhydrous magnesium sulfate and re move the solvent undervacuum. The solid product may be dissolved in methanol, concentrated abit, and cooled to cause precipitation of crystalline product.

EXAMPLE 7 1-Acetoxy-I7,17-Ethylenedioxy-4-Methylesn'a, 1,3,5(]0)-TrieneFirst dissolve 100 mg. of17,l7-ethylenedioxy-4-methylestra-l,3,5(10)-trien-1-ol in 10 ml. of drypyridine and add 3 m1. of acetic anhydride. After keeping at roomtemperature for 18 hours, evaporate the solvents under vacuum anddissolve the residual amorphous product in acetone. While boiling thesolution add hexane until crystallization commences. Cool the solutionand filter the crystalline product.

EXAMPLE 8 4-Methyl-17,17-Trimethylenedi0xyestm-1,3,5(10) T rien-I -OlReflux a mixture of 100 mg. of1-hydroxy-4-methylestra-1,3,5()-trien-l7-one, 25 ml. of benzene, 100 mg.of p-toluenesulfonic acid and 5 ml. of 1,3-propanediol for twenty hours.Cool the mixture, wash with saturated sodium bicarbonate solution andthen with water. Dry the benzene solution over anhydrous magnesiumsulfate and evaporate the solvent under vacuum. The solid residue may bedissolved in acetone and the solution concentrated until crystallizationcommences, at which time a small amount of hexane may be added. Leavestanding for several hours, and then filter and dry the crystallineproduct.

EXAMPLE 9 17,17-Eflzylenedithio-4-Methylestra-I,3,5(10)- T rien-l -OlCool a mixture of 500 mg. of 1-hydroxy-4-methylestra-1,3,5(10)-trien-17-one, 3 ml. of ethanedithiol, and ml. of chloroform to5 and bubble anhydrous hydrogen chloride through the solution for threehours. Then remove the solvent under vacuum and take up the residual gumin warm acetone. Concentrate the acetone solution somewhat and addhexane. The crystalline product crystallizes and may be recovered byfiltration.

EXAMPLE 10 1 7,1 7-Ethylenethi0xy-4-Methylestra-1,3,5 (10) T rien-J -OlReflux a solution containing 500 mg. of 1-hydroxy-4-methylestra-l,3,5(10)-trien-l7-one, 30 mg. of p-toluenesulfonic acid in75 ml. of dry benzene containing 2 ml. of Z-mercaptoethanol. After sixhours of reflux cool the mixture and wash it with saturated sodiumbicarbonate solution and then with water. Evaporate the benzene solutionand dissolve the residue in methanol. Concentrate the methanol solutionuntil crystallization begins and then cool to cause completeprecipitation of the crystalline product.

6 We claim: 1. A compound of the structural formula:

wherein R represents a substituent selected from the group consisting ofhydrogen, lower alkyl, lower alkenyl, lower cycloalkyl of up to 6 carbonatoms, lower aralkyl, and lower alkanoyl; R represents a lower alkylgroup; and W represents a member selected from the group consisting oflower alkylenedioxymethylene of up to 4 carbon atoms, loweralkylenethioxymethylene of up to 4 carbon atoms, and loweralkylenedithiomethylene of up to 4 carbon atoms.

2. A compound according to claim 1 wherein R represents hydrogen, Rrepresents lower alkyl and W represents lower alkylenedioxymethylene ofup to 4 carbon atoms.

3. 17,17-ethylenedioxy-4-methylestra 1,3,5 (IO-trien-lol.

4. 17,17-ethylenedioxy-1-methoxy-4-methylestra 1,3-5 (10) -triene.

5. l-ethoxy 17,17 ethylenedioxy-4-methylestra-1,3-5 (10)-triene.

6. 1-allyloxy-17,17-ethylenedioxy 4 methylestra-1,3,5 (10) -triene.

7. 1-benzyloxy-17,17-ethylenedioxy 4 methylestra-l, 3,5(10)-triene.

8. 4 methyl-17,17-trimethylenedioxyestra 1,3,5 (10)- trien-l-ol.

9. 17,17-ethylenedithio-4-methylestra 1,3,5 l0)-trien- 1-ol.

10. 17,17 ethylenethioxy-4-methylestra 1,3,5 10)- trien-l-ol.

11. l-acetoxy 17,17 ethylenedioxy-4-methylestra-1,3, 5(10)-triene.

References Cited in the file of this patent Gentles et al.: I.A.C.S.,vol. 80, pp. 3702-05 (1958). Lowenthal: Tetrahedran, vol. 6, pp. 269-303(1959). Dannenberg et al.: Justus Liebigs Annalen der Chemie Bd. 646,pp. 148-169 (1961).

1. A COMPOUND OF THE STRUCTURAL FORMULA: